Browsing by Author "Schoenmakers, Nadia A."

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    A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism
    (Walter De Gruyter Gmbh, 2014-07) Cangül, Hakan; Schoenmakers, Nadia A.; Saǧlam, Yaman; Kendall, Michaela; Timothy Barrett, Timothy; Chatterjee, Krish; Mäher, Eamonn Richard; Saǧlam, Halil; Doğanlar, Durmuş; Eren, Erdal; Tarım, Ömer Faruk; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Endokrinoloji Anabilim Dalı.; 0000-0003-0710-5422; 0000-0002-1684-1053; C-7392-2019; AAH-1155-2021; 35612700100; 56363214600; 36113153400; 6701427186
    Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have a familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. As CH is often inherited in an autosomal recessive manner in consanguineous/multi case-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene. The family showed potential linkage to the TSHR locus and our attempts to amplify and sequence exon 2 of the TSHR gene continuously failed. Subsequent RT-PCR analysis using mRNA and corresponding cDNA showed a large deletion including the exon 2 of the gene. The deletion was homozygous in affected cases whilst heterozygous in carrier parents. Here we conclude that CH in both siblings of this study originates from a large deletion including the exon 2 of the TSHR gene. This study demonstrates that full sequence analysis in a candidate CH gene might not always be enough to detect genetic alterations, and additional analyses such as RT-PCR and MLPA might be necessary to describe putative genetic causes of the disease in some cases. It also underlines the importance of detailed molecular genetic studies in the definitive diagnosis and classification of CH.
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    Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community
    (Wiley, 2013-08) Cangül, Hakan; Aycan, Zehra; Nappa, Alvaro Olivera; Schoenmakers, Nadia A.; Boelaert, Kristien; Çetinkaya, Semra Çaǧlar; Böber, Ece; Darendeliler, Feyza F.; Baş, Veysel Nijat; Demir, Korcan; Saǧlam, Halil; Tarım, Ömer Faruk; Uludağ Üniversitesi/Tıp Fakültesi/Pediatrik Endokrinoloji Anabilim Dalı.; 0000-0003-0710-5422; C-7392-2019; 35612700100; 6701427186
    Objective In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH). Context Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease. Design As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families. Patients One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families. Measurements Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out. Results TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N). Conclusions This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases.